Moderna and Merck’s Personalized mRNA Vaccine Cuts Melanoma Recurrence Risk by 49% at Five Years

More than five years after patients with high-risk melanoma received an experimental therapy tailored to the unique genetic code of their own tumors, the benefits remain clear. A personalized mRNA cancer vaccine developed by Moderna and Merck, used alongside the immunotherapy Keytruda, has sustained a 49% reduction in the risk of cancer recurrence or death—with no sign of the protective effect fading over time.

These findings, from the Phase 2b KEYNOTE-942 trial, represent the longest follow-up data yet for a personalized mRNA cancer vaccine in a randomized clinical trial. Presented at the 2026 ASCO Annual Meeting, the results solidify the promise of individualized neoantigen therapy (INT) and have already propelled the treatment into multiple large-scale, registration-enabling Phase 3 studies .

Five-Year Results: Durable and Deep Protection

The KEYNOTE-942 (mRNA-4157-P201) trial enrolled patients with resected, high-risk stage III/IV melanoma. All participants received pembrolizumab (Keytruda), the current standard-of-care checkpoint inhibitor. Half were randomized to also receive intismeran autogene (mRNA-4157/V940), a custom-built mRNA vaccine.

At a median planned follow-up of 60.3 months, the combination arm showed :

• 49% reduction in the risk of recurrence or death versus pembrolizumab alone (hazard ratio 0.510; 95% CI, 0.294–0.887).
• 59% reduction in the risk of distant metastasis or death compared to the control group.

Crucially, the separation between the treatment and control curves did not diminish over the full five-year window. Analysts noted this stability suggests the vaccine successfully reprograms the adaptive immune system for long-term surveillance, rather than providing only a transient boost .

How a Bespoke mRNA Vaccine Trains the Immune System

Intismeran autogene belongs to a new class of medicines called mRNA-based individualized neoantigen therapies. Unlike traditional vaccines that target a common pathogen, each dose is manufactured for a single patient after analyzing their surgically removed tumor .

The multi-step process works as follows :

1. Tumor Sequencing: Whole exome and RNA sequencing identifies the unique set of somatic mutations present in a patient's tumor.
2. Neoantigen Selection: Proprietary machine learning algorithms select up to 34 of the most immunogenic mutation-associated neoantigens (MANAs)—abnormal protein fragments displayed only on cancer cells.
3. Custom mRNA Manufacturing: A synthetic mRNA strand encoding those patient-specific neoantigens is produced and encapsulated in solid lipid nanoparticles.
4. Intramuscular Injection: Once administered, the mRNA instructs the patient's own cells to manufacture the neoantigen proteins, which are then processed and presented to the immune system.
5. T-Cell Priming: The presentation of these foreign neoantigens induces strong neoantigen-specific CD8+ and CD4+ T-cell responses, effectively providing the immune system with precise "GPS coordinates" to seek and destroy any tumor cell bearing those mutations.

The combination with pembrolizumab exploits complementary immune pathways. The vaccine delivers the priming "teach" signal, generating new waves of cancer-specific T cells, while pembrolizumab blocks the PD-1 checkpoint to "release the brakes" on those T cells, allowing a sustained, aggressive attack on residual cancer cells .

What’s Next: From Melanoma to Lung Cancer and Beyond

The five-year durability data significantly de-risks the platform, but the therapy remains investigational. No regulatory approvals have been granted yet . The future of intismeran autogene now rests on the outcomes of several large Phase 3 trials.

Adjuvant Melanoma (V940-001)

A global, randomized, double-blind, placebo-controlled Phase 3 trial is comparing intismeran autogene plus pembrolizumab against placebo plus pembrolizumab in patients with resected, high-risk stage IIB–IV melanoma . Enrollment began in mid-2023, with the first patients enrolling in Australia. This is the registration-enabling study intended to support regulatory submissions for the adjuvant melanoma indication .

Non-Small Cell Lung Cancer (INTerpath-009)

In October 2024, Merck and Moderna initiated INTerpath-009, a pivotal Phase 3 trial evaluating the same combination in a completely different tumor type. The study targets 680 patients with resectable stage II to IIIB (N2) non-small cell lung cancer (NSCLC) who did not achieve a pathological complete response after receiving neoadjuvant pembrolizumab plus platinum-based chemotherapy . This trial, with disease-free survival as its primary endpoint, is the third Phase 3 study in the broader INTerpath program, confirming the partners’ ambition to test the personalized mRNA platform across multiple early-stage, high-risk cancer settings .

Beyond melanoma and lung cancer, additional trials are exploring the combination in renal cell carcinoma, urothelial carcinoma, and cutaneous squamous cell carcinoma, making intismeran autogene the most clinically advanced personalized mRNA neoantigen therapy in oncology .